chr18-46533320-G-A

Variant names:

• chr18-46533320-G-A
• rs146739496
• NM_001384474.1:c.4217C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001384474.1(LOXHD1):​c.4217C>T​(p.Ala1406Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,551,524 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (30 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 9.57
• Publications: 17 publications found

Genes affected

LOXHD1 (HGNC:26521): (lipoxygenase homology PLAT domains 1) This gene encodes a highly conserved protein consisting entirely of PLAT (polycystin/lipoxygenase/alpha-toxin) domains, thought to be involved in targeting proteins to the plasma membrane. Studies in mice show that this gene is expressed in the mechanosensory hair cells in the inner ear, and mutations in this gene lead to auditory defects, indicating that this gene is essential for normal hair cell function. Screening of human families segregating deafness identified a mutation in this gene which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2010]

LOXHD1 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 77

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068620443).
• BP6: Variant 18-46533320-G-A is Benign according to our data. Variant chr18-46533320-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178397.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00198 (301/152344) while in subpopulation SAS AF = 0.0164 (79/4820). AF 95% confidence interval is 0.0135. There are 0 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 30 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384474.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.4217C>T	p.Ala1406Val	missense	Exon 28 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.4217C>T	p.Ala1406Val	missense	Exon 28 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.884C>T	p.Ala295Val	missense	Exon 10 of 24	NP_001138944.1	Q8IVV2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.4217C>T	p.Ala1406Val	missense	Exon 28 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.884C>T	p.Ala295Val	missense	Exon 10 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.596C>T	p.Ala199Val	missense	Exon 8 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00399 AC: 634 AN: 158722 AF XY: 0.00493

Gnomad AFR exome AF: 0.000227

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.0000884

Gnomad FIN exome AF: 0.000355

Gnomad NFE exome AF: 0.00269

Gnomad OTH exome AF: 0.00335

GnomAD4 exome AF: 0.00253 AC: 3546 AN: 1399180 Hom.: 30 Cov.: 31 AF XY: 0.00297 AC XY: 2053 AN XY: 690102

African (AFR) AF: 0.000602 AC: 19 AN: 31574

American (AMR) AF: 0.00211 AC: 75 AN: 35620

Ashkenazi Jewish (ASJ) AF: 0.000755 AC: 19 AN: 25170

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35738

South Asian (SAS) AF: 0.0158 AC: 1251 AN: 79186

European-Finnish (FIN) AF: 0.000142 AC: 7 AN: 49308

Middle Eastern (MID) AF: 0.0135 AC: 77 AN: 5692

European-Non Finnish (NFE) AF: 0.00176 AC: 1902 AN: 1078890

Other (OTH) AF: 0.00336 AC: 195 AN: 58002

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.00201 AC XY: 150 AN XY: 74498

African (AFR) AF: 0.000289 AC: 12 AN: 41586

American (AMR) AF: 0.00255 AC: 39 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4820

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00226 AC: 154 AN: 68036

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00214 Hom.: 6

Bravo AF: 0.00215

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00189 AC: 6

ExAC AF: 0.00686 AC: 179

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	Autosomal recessive nonsyndromic hearing loss 77 (5)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.77	T
PhyloP100		9.6
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.22
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.034	D
Polyphen		0.91	P
Vest4		0.053
MVP		0.21
ClinPred		0.079	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.47
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs146739496; hg19: chr18-44113283; COSMIC: COSV106095976;